TY - JOUR
T1 - Upregulation of ZIP14 and altered zinc homeostasis in muscles in pancreatic cancer cachexia
AU - Shakri, Ahmad Rushdi
AU - Zhong, Timothy James
AU - Ma, Wanchao
AU - Coker, Courtney
AU - Kim, Sean
AU - Calluori, Stephanie
AU - Scholze, Hanna
AU - Szabolcs, Matthias
AU - Caffrey, Thomas
AU - Grandgenett, Paul M.
AU - Hollingsworth, Michael A.
AU - Tanji, Kurenai
AU - Kluger, Michael D.
AU - Miller, George
AU - Biswas, Anup Kumar
AU - Acharyya, Swarnali
N1 - Funding Information:
Acknowledgments: The authors would like to thank the members of their laboratory for their insights in this study. This study used the resources of the Herbert Irving Comprehensive Cancer Center Shared Resources (Molecular Pathology) funded in part through the Cancer Center grant 5P30CA013696.
Funding Information:
CTSA grant UL1TR001873, Interdisciplinary Research Initiatives Seed (IRIS) Funds from CUIMC, and The Irma T. Hirschl Monique Weill-Caulier Charitable Trusts to S.A.
Funding Information:
Funding: This work was supported by NYU 18-S1-00-006678 subaward (G.M. and S.A.), NCI R01 CA231239, Institutional start-up funds from CUIMC, by Herbert Irving Comprehensive Cancer Center’s 5P30CA013696-43 Cancer Center Support Grant-Inter-Programmatic Pilot Project, Irving Scholars Program from the Irving Institute
Funding Information:
This work was supported by NYU 18-S1-00-006678 subaward (G.M. and S.A.), NCI R01 CA231239, Institutional start-up funds from CUIMC, by Herbert Irving Comprehensive Cancer Center?s 5P30CA013696-43 Cancer Center Support Grant-Inter-Programmatic Pilot Project, Irving Scholars Program from the Irving Institute CTSA grant UL1TR001873, Interdisciplinary Research Initiatives Seed (IRIS) Funds from CUIMC, and The Irma T. Hirschl Monique Weill-Caulier Charitable Trusts to S.A. The authors would like to thank the members of their laboratory for their insights in this study. This study used the resources of the Herbert Irving Comprehensive Cancer Center Shared Resources (Molecular Pathology) funded in part through the Cancer Center grant 5P30CA013696.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/1
Y1 - 2020/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type in which the mortality rate approaches the incidence rate. More than 85% of PDAC patients experience a profound loss of muscle mass and function, known as cachexia. PDAC patients with this condition suffer from decreased tolerance to anti-cancer therapies and often succumb to premature death due to respiratory and cardiac muscle wasting. Yet, there are no approved therapies available to alleviate cachexia. We previously found that upregulation of the metal ion transporter, Zip14, and altered zinc homeostasis are critical mediators of cachexia in metastatic colon, lung, and breast cancer models. Here, we show that a similar mechanism is likely driving the development of cachexia in PDAC. In two independent experimental metastasis models generated from the murine PDAC cell lines, Pan02 and FC1242, we observed aberrant Zip14 expression and increased zinc ion levels in cachectic muscles. Moreover, in advanced PDAC patients, high levels of ZIP14 in muscles correlated with the presence of cachexia. These studies underscore the importance of altered ZIP14 function in PDAC-associated cachexia development and highlight a potential therapeutic opportunity for improving the quality of life and prolonging survival in PDAC patients.
AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type in which the mortality rate approaches the incidence rate. More than 85% of PDAC patients experience a profound loss of muscle mass and function, known as cachexia. PDAC patients with this condition suffer from decreased tolerance to anti-cancer therapies and often succumb to premature death due to respiratory and cardiac muscle wasting. Yet, there are no approved therapies available to alleviate cachexia. We previously found that upregulation of the metal ion transporter, Zip14, and altered zinc homeostasis are critical mediators of cachexia in metastatic colon, lung, and breast cancer models. Here, we show that a similar mechanism is likely driving the development of cachexia in PDAC. In two independent experimental metastasis models generated from the murine PDAC cell lines, Pan02 and FC1242, we observed aberrant Zip14 expression and increased zinc ion levels in cachectic muscles. Moreover, in advanced PDAC patients, high levels of ZIP14 in muscles correlated with the presence of cachexia. These studies underscore the importance of altered ZIP14 function in PDAC-associated cachexia development and highlight a potential therapeutic opportunity for improving the quality of life and prolonging survival in PDAC patients.
KW - Cachexia
KW - Metastasis
KW - Muscle atrophy
KW - Pancreatic cancer
KW - Pancreatic ductal adenocarcinoma
KW - Slc39a14
KW - ZIP14
KW - Zinc homeostasis
KW - Zinc transporter
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UR - http://www.scopus.com/inward/citedby.url?scp=85077572344&partnerID=8YFLogxK
U2 - 10.3390/cancers12010003
DO - 10.3390/cancers12010003
M3 - Article
C2 - 31861290
AN - SCOPUS:85077572344
SN - 2072-6694
VL - 12
JO - Cancers
JF - Cancers
IS - 1
M1 - 3
ER -